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Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01862328
Collaborator
(none)
64
Enrollment
6
Locations
3
Arms
59.3
Actual Duration (Months)
10.7
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to establish the maximum tolerated dose (MTD) and assess the safety and tolerability of MLN4924 (pevonedistat) in combination with docetaxel, paclitaxel and carboplatin, and gemcitabine in participants with solid tumors.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
64 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors
Actual Study Start Date :
Jun 10, 2013
Actual Primary Completion Date :
May 21, 2018
Actual Study Completion Date :
May 21, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: MLN4924 and Docetaxel (Arm 1)

Drug: MLN4924
MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle
Other Names:
  • Pevonedistat

    • Drug: Docetaxel
    Docetaxel (IV) in participants in a 21-day cycle: - Docetaxel on Day 1 of each cycle
    Experimental: MLN4924 + Paclitaxel + Carboplatin (Arm 2)

    Drug: MLN4924
    MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle
    Other Names:
  • Pevonedistat

    • Drug: Paclitaxel
    Paclitaxel (IV) in a 21-day cycle: Paclitaxel on Day 1 of each cycle

    Drug: Carboplatin
    Carboplatin (IV) in participants in a 21-day cycle: - Carboplatin on Day 1 of each cycle
    Experimental: MLN4924 + Gemcitabine (Arm 3)

    Drug: MLN4924
    MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle
    Other Names:
  • Pevonedistat

    • Drug: Gemcitabine
    Gemcitabine (IV) in participants in a 28-day cycle: -Gemcitabine on Days 1,8,15 of each cycle

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to 30 days after the last dose of study drug (up to 5 years)]

    2. Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings [Baseline up to 30 days after the last dose of study drug (up to 5 years)]

    3. Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings [Baseline up to 30 days after the last dose of study drug (up to 5 years)]

    Secondary Outcome Measures

    1. Percentage of Participants With Objective Response [Screening, Cycle 2 Days 15 (Arm 1, 2a, and 2) and 22 (Arm 3) then every other Cycle thereafter up to 30 days after the last dose of study drug (up to 5 years) (Cycle Length = 21 days [Arm 1, 2a, and 2] and 28 days [Arm 3])]

      Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]); no new lesions. PR: greater than or equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions.

    2. Duration of Response [From the date of first documented response (CR or PR) to the date of first documented PD or the date of last disease assessment if the participants discontinued the study before PD (up to 5 years)]

      Duration of response: time from the date of first documented response per the investigator response assessment (CR or PR) to the date of PD or the date of last disease assessment if the participant discontinued the study before PD using RECIST 1.1 CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis <10 mm); no new lesions. PR: >=30% decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in sum of diameters of target lesions, taking as reference smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

    3. Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924 [Cycle 1 Day 1 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2] and 28 days [Arm 3])]

    4. MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924 [Cycle 1 Days 1 and 5 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2])]

      The number of participants analyzed includes only those participants who had data available for this measure.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. 18 years of age or older

    2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

    3. Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with 1 of the 3 chemotherapy regimens in this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable

    4. Recovered (that is, <=Grade 1 toxicity) from the effects of prior antineoplastic therapy

    5. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence

    6. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence

    7. Voluntary written consent must be given before performance of any study-related procedure

    8. Suitable venous access for the study-required blood sampling

    9. Adequate clinical laboratory values during the screening period as specified in the protocol

    10. Participants who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male participants) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924

    11. Availability of fixed tumor specimen (block or slides) for exploratory biomarker analysis. If no slides or block are available, fresh tumor biopsies should be obtained and used for these assessments

    Exclusion Criteria:

    1. Major surgery within 14 days before the first dose of study drug

    2. Female participants who are lactating or pregnant

    3. Active uncontrolled infection or severe infectious disease

    4. Receiving antibiotic therapy within 14 days before the first dose of study treatment

    5. Life-threatening illness unrelated to cancer

    6. Known hypersensitivity to study-assigned chemotherapy

    7. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel,carboplatin, and gemcitabine is allowed

    8. History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for participants to be enrolled in Arm 1 (MLN4924 + docetaxel), history of hypersensitivity to carboplatin for participants to be enrolled in Arm 2 (MLN4924 + paclitaxel + carboplatin), or history of severe hypersensitivity to paclitaxel (cremophor-based formulations) for participants to be enrolled in Arm 2

    9. Persistent diarrhea (greater than Grade 2) lasting >3 days within 2 weeks before the first dose of study treatment

    10. Systemic antineoplastic therapy within 21 days before the first dose of study drug

    11. Radiotherapy within 14 days preceding the first dose of study treatment

    12. Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow

    13. Treatment with cytochrome P450 3A (CYP3A) inducers within 14 days before the first dose of MLN4924.

    Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924; however, voriconazole and fluconazole need only be stopped for 3 days before MLN4924. Participants must have no history of amiodarone use in the 6 months before the first dose of MLN4924 14. Clinically uncontrolled central nervous system (CNS) involvement 15. Any serious medical or psychiatric illness 16. Treatment with any investigational products 21 days prior to treatment 17. Unwilling or unable to refrain from using statins 24 hours before, the day of, and 24 hours after each MLN4924 administration 18. Known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 19. Known hepatic cirrhosis 20. Known cardiac/cardiopulmonary disease 21. Left ventricular ejection fraction 23. with a cardiac pacer whose heart rate is set at a fixed rate and participants on concomitant medication that may limit increase in heart rate in response to hypotension 24 History of severe intolerance to cytotoxic agent(s) given in the assigned arm

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Atlanta Georgia United States 30322
    2 Saint Louis Missouri United States 63110
    3 Chapel Hill North Carolina United States 27599
    4 Cleveland Ohio United States 44106-4948
    5 Philadelphia Pennsylvania United States 19104
    6 Nashville Tennessee United States 37203

    Sponsors and Collaborators

    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT01862328
    Other Study ID Numbers:
    • C15010
    • U1111-1220-1470
    First Posted:
    May 24, 2013
    Last Update Posted:
    Jun 22, 2020
    Last Verified:
    Jun 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by Millennium Pharmaceuticals, Inc.
    MLN4924
    Solid Tumors
    Additional relevant MeSH terms:
    Neoplasms
    Gemcitabine
    Paclitaxel
    Docetaxel
    Carboplatin
    Pevonedistat

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 6 investigative sites in the United States from 10 June 2013 to 21 May 2018.
    Pre-assignment Detail Participants with solid tumors were enrolled to receive MLN4924 in combination with docetaxel (Arm 1), paclitaxel + carboplatin (Arm 2), or gemcitabine (Arm 3) during the Dose-escalation and maximum tolerated dose (MTD) expansion portion of this study. Participants in Lead-in cohort received MLN4924 + carboplatin only (Arm 2a).
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or progressive disease (PD) (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Period Title: Overall Study
    STARTED 4 18 6 7 12 7 10
    COMPLETED 0 0 0 0 0 0 0
    NOT COMPLETED 4 18 6 7 12 7 10

    Baseline Characteristics

    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2 Total
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52). Total of all reporting groups
    Overall Participants 4 18 6 7 12 7 10 64
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    57.8
    (2.99)
    60.0
    (9.82)
    56.8
    (9.56)
    58.1
    (10.65)
    57.9
    (14.34)
    59.0
    (12.00)
    59.7
    (14.45)
    58.8
    (11.19)
    Sex: Female, Male (Count of Participants)
    Female
    2
    50%
    11
    61.1%
    4
    66.7%
    4
    57.1%
    8
    66.7%
    1
    14.3%
    4
    40%
    34
    53.1%
    Male
    2
    50%
    7
    38.9%
    2
    33.3%
    3
    42.9%
    4
    33.3%
    6
    85.7%
    6
    60%
    30
    46.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    10%
    2
    3.1%
    Not Hispanic or Latino
    3
    75%
    14
    77.8%
    6
    100%
    7
    100%
    11
    91.7%
    7
    100%
    7
    70%
    55
    85.9%
    Unknown or Not Reported
    1
    25%
    3
    16.7%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    2
    20%
    7
    10.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    25%
    5
    27.8%
    2
    33.3%
    2
    28.6%
    1
    8.3%
    0
    0%
    1
    10%
    12
    18.8%
    White
    3
    75%
    13
    72.2%
    4
    66.7%
    5
    71.4%
    11
    91.7%
    7
    100%
    9
    90%
    52
    81.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    4
    100%
    18
    100%
    6
    100%
    7
    100%
    12
    100%
    7
    100%
    10
    100%
    64
    100%
    Body surface area (BSA) (square meter (m^2)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [square meter (m^2)]
    1.9
    (0.32)
    1.9
    (0.28)
    1.8
    (0.29)
    2.0
    (0.28)
    1.9
    (0.32)
    1.9
    (0.17)
    1.9
    (0.25)
    1.9
    (0.27)

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    Description
    Time Frame Baseline up to 30 days after the last dose of study drug (up to 5 years)

    Outcome Measure Data

    Analysis Population Description
    The safety population was defined as all participants who received at least 1 dose of any study drug.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 4 18 6 7 12 7 10
    TEAE
    4
    100%
    18
    100%
    6
    100%
    7
    100%
    12
    100%
    7
    100%
    10
    100%
    SAE
    1
    25%
    9
    50%
    3
    50%
    2
    28.6%
    3
    25%
    1
    14.3%
    7
    70%
    2. Primary Outcome
    Title Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings
    Description
    Time Frame Baseline up to 30 days after the last dose of study drug (up to 5 years)

    Outcome Measure Data

    Analysis Population Description
    The safety population was defined as all participants who received at least 1 dose of any study drug.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 4 18 6 7 12 7 10
    Anaemia
    1
    25%
    4
    22.2%
    2
    33.3%
    2
    28.6%
    7
    58.3%
    2
    28.6%
    3
    30%
    Aspartate aminotransferase increased
    0
    0%
    6
    33.3%
    2
    33.3%
    2
    28.6%
    5
    41.7%
    2
    28.6%
    2
    20%
    Alanine aminotransferase increased
    0
    0%
    7
    38.9%
    1
    16.7%
    1
    14.3%
    4
    33.3%
    1
    14.3%
    3
    30%
    Neutrophil count decreased
    1
    25%
    5
    27.8%
    1
    16.7%
    3
    42.9%
    3
    25%
    1
    14.3%
    1
    10%
    Neutropenia
    1
    25%
    1
    5.6%
    1
    16.7%
    1
    14.3%
    4
    33.3%
    4
    57.1%
    3
    30%
    Thrombocytopenia
    0
    0%
    1
    5.6%
    3
    50%
    1
    14.3%
    3
    25%
    3
    42.9%
    3
    30%
    Platelet count decreased
    0
    0%
    1
    5.6%
    2
    33.3%
    3
    42.9%
    2
    16.7%
    2
    28.6%
    3
    30%
    White blood cell count decreased
    1
    25%
    2
    11.1%
    0
    0%
    0
    0%
    4
    33.3%
    0
    0%
    0
    0%
    Hypomagnesaemia
    0
    0%
    2
    11.1%
    2
    33.3%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    Blood creatinine increased
    1
    25%
    2
    11.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    10%
    Blood alkaline phosphatase increased
    0
    0%
    2
    11.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    10%
    Lymphocyte count decreased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    1
    8.3%
    1
    14.3%
    0
    0%
    Blood bilirubin increased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    1
    10%
    Hypophosphataemia
    0
    0%
    2
    11.1%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    Hypokalaemia
    1
    25%
    0
    0%
    1
    16.7%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    Gamma-glutamyltransferase increased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    Blood glucose increased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Liver function test abnormal
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Haematocrit decreased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Red blood cell count decreased
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypoglycaemia
    0
    0%
    1
    5.6%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    Hyponatraemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings
    Description
    Time Frame Baseline up to 30 days after the last dose of study drug (up to 5 years)

    Outcome Measure Data

    Analysis Population Description
    The safety population was defined as all participants who received at least 1 dose of any study drug.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 4 18 6 7 12 7 10
    Tachycardia
    0
    0%
    2
    11.1%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypotension
    1
    25%
    3
    16.7%
    2
    33.3%
    2
    28.6%
    0
    0%
    2
    28.6%
    1
    10%
    4. Secondary Outcome
    Title Percentage of Participants With Objective Response
    Description Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]); no new lesions. PR: greater than or equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions.
    Time Frame Screening, Cycle 2 Days 15 (Arm 1, 2a, and 2) and 22 (Arm 3) then every other Cycle thereafter up to 30 days after the last dose of study drug (up to 5 years) (Cycle Length = 21 days [Arm 1, 2a, and 2] and 28 days [Arm 3])

    Outcome Measure Data

    Analysis Population Description
    The response-evaluable population was defined as all the participants who received at least 1 dose of MLN4924, had measurable disease at baseline, and had at least 1 post baseline disease assessment.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 3 16 6 7 11 5 6
    CR
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    18
    150%
    0
    0%
    0
    0%
    PR
    0
    0%
    19
    105.6%
    17
    283.3%
    0
    0%
    36
    300%
    40
    571.4%
    0
    0%
    5. Secondary Outcome
    Title Duration of Response
    Description Duration of response: time from the date of first documented response per the investigator response assessment (CR or PR) to the date of PD or the date of last disease assessment if the participant discontinued the study before PD using RECIST 1.1 CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis <10 mm); no new lesions. PR: >=30% decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in sum of diameters of target lesions, taking as reference smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
    Time Frame From the date of first documented response (CR or PR) to the date of first documented PD or the date of last disease assessment if the participants discontinued the study before PD (up to 5 years)

    Outcome Measure Data

    Analysis Population Description
    The response-evaluable population is defined as all participants who receive at least 1 dose of study drug, have measurable disease at baseline, and have at least 1 post baseline disease assessment. The number of participants analyzed includes only those participants who had data available for this measure.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 0 3 1 0 6 2 0
    Mean (Standard Deviation) [months]
    2.880
    (2.7644)
    2.270
    (NA)
    16.153
    (15.9867)
    7.015
    (1.1384)
    6. Secondary Outcome
    Title Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924
    Description
    Time Frame Cycle 1 Day 1 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2] and 28 days [Arm 3])

    Outcome Measure Data

    Analysis Population Description
    The safety population was defined as all participants who received at least 1 dose of any study drug. The number of participants analyzed includes only those participants who had data available for this measure. This outcome measure was planned to be assessed only in the Dose-escalation phases of Arms 1, 2, and 3.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 4 18 7 12 7 10
    Cycle 1 Day 1: End-dose
    163.8
    (109.15)
    197.1
    (51.94)
    275.7
    (98.67)
    257.3
    (110.05)
    372.7
    (120.93)
    222.0
    (87.62)
    Cycle 1 Day 1: 1.5 hours post dose
    82.0
    (39.97)
    130.6
    (46.94)
    156.8
    (53.46)
    192.7
    (80.35)
    246.7
    (47.24)
    160.5
    (122.07)
    Cycle 1 Day 1: 3 hours post dose
    48.0
    (12.05)
    95.8
    (19.70)
    152.4
    (56.19)
    138.0
    (73.10)
    186.9
    (32.30)
    103.0
    (39.00)
    Cycle 1 Day 1: 20 hours post dose
    7.5
    (1.50)
    14.6
    (4.81)
    23.4
    (9.19)
    34.6
    (25.09)
    24.4
    (10.81)
    14.2
    (5.09)
    7. Secondary Outcome
    Title MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924
    Description The number of participants analyzed includes only those participants who had data available for this measure.
    Time Frame Cycle 1 Days 1 and 5 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2])

    Outcome Measure Data

    Analysis Population Description
    The safety population was defined as all participants who received at least 1 dose of any study drug. This outcome measure was planned to be assessed for participants who received the MTD in Arms 1 and 2.
    Arm/Group Title Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5
    Arm/Group Description MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    Measure Participants 18 12
    Cycle 1 Day 1: End-dose
    152.8
    (83.67)
    429.8
    (95.87)
    Cycle 1 Day 1: 1.5 hours post dose
    137.3
    (37.19)
    253.6
    (19.65)
    Cycle 1 Day 1: 3 hours post dose
    86.4
    (29.16)
    192.8
    (39.14)
    Cycle 1 Day 1: 6 hours post dose
    136.3
    (14.73)
    Cycle 1 Day 1: 7 hours post dose
    63.4
    (24.87)
    Cycle 1 Day 1: 20 hours post dose
    14.2
    (5.39)
    30.2
    (7.98)
    Cycle 1 Day 5: End-dose
    211.1
    (116.43)
    253.2
    (56.60)
    Cycle 1 Day 5: 1.5 hours post dose
    115.3
    (42.54)
    171.0
    (19.44)
    Cycle 1 Day 5: 3 hours post dose
    96.7
    (53.48)
    118.4
    (19.69)
    Cycle 1 Day 5: 6 hours post dose
    76.5
    (4.97)
    Cycle 1 Day 5: 7 hours post dose
    38.3
    (17.84)
    Cycle 1 Day 5: 20 hours post dose
    9.8
    (2.07)
    10.9
    (3.40)

    Adverse Events

    Time Frame TEAEs are adverse events that started after the first dose of study drug and no more than 30 days (up to 5 years) after the last dose of study drug
    Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Arm/Group Title Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Arm/Group Description MLN4924 15 milligram per square meter (mg/m^2), infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and docetaxel 75 mg/m^2, infusion, intravenously, once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and carboplatin AUC6, infusion intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 15 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 20 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5, infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 3, and 5 and paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 followed by carboplatin AUC5 infusion, intravenously once on Day 1 before administration of MLN4924 in a 21-day cycle up to symptomatic deterioration or PD (up to Cycle 52). MLN4924 25 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 and gemcitabine 1000 mg/m^2, infusion, intravenously, once on Days 1, 8, and 15 before administration of MLN4924 in a 28-day cycle up to symptomatic deterioration or PD (up to Cycle 52).
    All Cause Mortality
    Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 3/10 (30%)
    Serious Adverse Events
    Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/4 (25%) 9/18 (50%) 3/6 (50%) 2/7 (28.6%) 3/12 (25%) 1/7 (14.3%) 7/10 (70%)
    Blood and lymphatic system disorders
    Febrile neutropenia 0/4 (0%) 1/18 (5.6%) 1/6 (16.7%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 2/10 (20%)
    Cardiac disorders
    Acute coronary syndrome 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Gastrointestinal disorders
    Abdominal pain 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Nausea 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Vomiting 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Upper gastrointestinal haemorrhage 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    General disorders
    Fatigue 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Death 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Pyrexia 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Infections and infestations
    Influenza 0/4 (0%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Pneumonia 1/4 (25%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Bacteraemia 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Sepsis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Septic shock 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Investigations
    Electrocardiogram ST segment depression 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Liver function test increased 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Neutrophil count decreased 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Metabolism and nutrition disorders
    Metabolic acidosis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm of unknown primary site 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Uterine cancer 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Nervous system disorders
    Encephalopathy 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Headache 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Seizure 0/4 (0%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Hypoxia 0/4 (0%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Pneumonia aspiration 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Pneumonitis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Atelectasis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Vascular disorders
    Hypotension 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    Arm 1: MLN4924 15 mg/m^2 + Docetaxel 75 mg/m^2 Arm 1: MLN4924 25 mg/m^2 + Docetaxel 75 mg/m^2 Arm 2a: MLN4924 15 mg/m^2 + Carboplatin AUC6 Arm 2: MLN4924 15 mg/m^2+Paclitaxel 175mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 20 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 2:MLN4924 25 mg/m^2+Paclitaxel 175 mg/m^2+Carboplatin AUC5 Arm 3: MLN4924 25 mg/m^2 + Gemcitabine 1000 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 18/18 (100%) 6/6 (100%) 6/7 (85.7%) 12/12 (100%) 7/7 (100%) 10/10 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/4 (25%) 6/18 (33.3%) 3/6 (50%) 2/7 (28.6%) 8/12 (66.7%) 2/7 (28.6%) 4/10 (40%)
    Thrombocytopenia 0/4 (0%) 2/18 (11.1%) 3/6 (50%) 1/7 (14.3%) 3/12 (25%) 3/7 (42.9%) 3/10 (30%)
    Neutropenia 1/4 (25%) 1/18 (5.6%) 1/6 (16.7%) 1/7 (14.3%) 4/12 (33.3%) 4/7 (57.1%) 2/10 (20%)
    Leukopenia 1/4 (25%) 3/18 (16.7%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 2/10 (20%)
    Lymphopenia 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 2/10 (20%)
    Leukocytosis 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Cardiac disorders
    Tachycardia 0/4 (0%) 2/18 (11.1%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Extrasystoles 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Eye disorders
    Vision blurred 0/4 (0%) 1/18 (5.6%) 1/6 (16.7%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Lacrimation increased 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Eye irritation 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Visual impairment 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Gastrointestinal disorders
    Nausea 0/4 (0%) 8/18 (44.4%) 5/6 (83.3%) 3/7 (42.9%) 8/12 (66.7%) 3/7 (42.9%) 5/10 (50%)
    Constipation 1/4 (25%) 3/18 (16.7%) 4/6 (66.7%) 3/7 (42.9%) 5/12 (41.7%) 3/7 (42.9%) 3/10 (30%)
    Diarrhoea 3/4 (75%) 6/18 (33.3%) 1/6 (16.7%) 4/7 (57.1%) 6/12 (50%) 1/7 (14.3%) 1/10 (10%)
    Vomiting 0/4 (0%) 4/18 (22.2%) 1/6 (16.7%) 3/7 (42.9%) 6/12 (50%) 2/7 (28.6%) 3/10 (30%)
    Abdominal pain 0/4 (0%) 4/18 (22.2%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 1/7 (14.3%) 1/10 (10%)
    Abdominal distension 0/4 (0%) 3/18 (16.7%) 1/6 (16.7%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 1/10 (10%)
    Stomatitis 0/4 (0%) 5/18 (27.8%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Dry mouth 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 2/7 (28.6%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Dyspepsia 0/4 (0%) 1/18 (5.6%) 2/6 (33.3%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Dysphagia 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Oral pain 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Ascites 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    General disorders
    Fatigue 1/4 (25%) 11/18 (61.1%) 4/6 (66.7%) 5/7 (71.4%) 7/12 (58.3%) 5/7 (71.4%) 4/10 (40%)
    Pyrexia 1/4 (25%) 4/18 (22.2%) 1/6 (16.7%) 1/7 (14.3%) 2/12 (16.7%) 3/7 (42.9%) 2/10 (20%)
    Oedema peripheral 2/4 (50%) 1/18 (5.6%) 1/6 (16.7%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 3/10 (30%)
    Asthenia 1/4 (25%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 3/12 (25%) 2/7 (28.6%) 1/10 (10%)
    Pain 0/4 (0%) 2/18 (11.1%) 1/6 (16.7%) 2/7 (28.6%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Chills 0/4 (0%) 1/18 (5.6%) 2/6 (33.3%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Non-cardiac chest pain 1/4 (25%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Chest discomfort 0/4 (0%) 0/18 (0%) 2/6 (33.3%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Chest pain 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Localised oedema 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Malaise 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Oedema 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Hepatobiliary disorders
    Portal vein thrombosis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Immune system disorders
    Multiple allergies 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Infections and infestations
    Urinary tract infection 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 2/7 (28.6%) 4/12 (33.3%) 1/7 (14.3%) 1/10 (10%)
    Upper respiratory tract infection 2/4 (50%) 1/18 (5.6%) 1/6 (16.7%) 2/7 (28.6%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Cellulitis 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Epididymitis 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Oral candidiasis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 1/7 (14.3%) 0/10 (0%)
    Sepsis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Injury, poisoning and procedural complications
    Contusion 1/4 (25%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Infusion related reaction 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Investigations
    Aspartate aminotransferase increased 0/4 (0%) 6/18 (33.3%) 2/6 (33.3%) 2/7 (28.6%) 5/12 (41.7%) 2/7 (28.6%) 3/10 (30%)
    Alanine aminotransferase increased 0/4 (0%) 7/18 (38.9%) 1/6 (16.7%) 1/7 (14.3%) 4/12 (33.3%) 1/7 (14.3%) 4/10 (40%)
    Neutrophil count decreased 1/4 (25%) 4/18 (22.2%) 1/6 (16.7%) 3/7 (42.9%) 3/12 (25%) 1/7 (14.3%) 1/10 (10%)
    Platelet count decreased 0/4 (0%) 1/18 (5.6%) 2/6 (33.3%) 3/7 (42.9%) 2/12 (16.7%) 2/7 (28.6%) 3/10 (30%)
    White blood cell count decreased 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 5/12 (41.7%) 0/7 (0%) 0/10 (0%)
    Blood alkaline phosphatase increased 1/4 (25%) 4/18 (22.2%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Blood creatinine increased 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 0/7 (0%) 1/10 (10%)
    Weight increased 1/4 (25%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 3/12 (25%) 0/7 (0%) 0/10 (0%)
    Blood bilirubin increased 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 1/10 (10%)
    Lymphocyte count decreased 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 1/7 (14.3%) 0/10 (0%)
    Platelet count increased 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Metabolism and nutrition disorders
    Decreased appetite 1/4 (25%) 3/18 (16.7%) 0/6 (0%) 3/7 (42.9%) 3/12 (25%) 0/7 (0%) 5/10 (50%)
    Dehydration 0/4 (0%) 3/18 (16.7%) 2/6 (33.3%) 2/7 (28.6%) 1/12 (8.3%) 2/7 (28.6%) 1/10 (10%)
    Hypomagnesaemia 0/4 (0%) 3/18 (16.7%) 2/6 (33.3%) 1/7 (14.3%) 2/12 (16.7%) 1/7 (14.3%) 1/10 (10%)
    Hypokalaemia 1/4 (25%) 4/18 (22.2%) 1/6 (16.7%) 0/7 (0%) 2/12 (16.7%) 1/7 (14.3%) 0/10 (0%)
    Hyponatraemia 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 1/7 (14.3%) 1/10 (10%)
    Hyperglycaemia 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 1/10 (10%)
    Hypophosphataemia 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Hypoalbuminaemia 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Hypophagia 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Hyperkalaemia 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Gout 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Metabolic acidosis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/4 (25%) 1/18 (5.6%) 0/6 (0%) 3/7 (42.9%) 3/12 (25%) 4/7 (57.1%) 2/10 (20%)
    Myalgia 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 2/7 (28.6%) 6/12 (50%) 2/7 (28.6%) 0/10 (0%)
    Pain in extremity 0/4 (0%) 1/18 (5.6%) 2/6 (33.3%) 2/7 (28.6%) 1/12 (8.3%) 0/7 (0%) 1/10 (10%)
    Back pain 0/4 (0%) 1/18 (5.6%) 1/6 (16.7%) 1/7 (14.3%) 1/12 (8.3%) 2/7 (28.6%) 0/10 (0%)
    Bone pain 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 1/7 (14.3%) 1/12 (8.3%) 1/7 (14.3%) 0/10 (0%)
    Flank pain 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 1/12 (8.3%) 1/7 (14.3%) 0/10 (0%)
    Groin pain 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 1/10 (10%)
    Joint swelling 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Muscle spasms 0/4 (0%) 0/18 (0%) 0/6 (0%) 2/7 (28.6%) 2/12 (16.7%) 1/7 (14.3%) 1/10 (10%)
    Nervous system disorders
    Peripheral sensory neuropathy 0/4 (0%) 3/18 (16.7%) 1/6 (16.7%) 3/7 (42.9%) 4/12 (33.3%) 2/7 (28.6%) 1/10 (10%)
    Dizziness 0/4 (0%) 2/18 (11.1%) 1/6 (16.7%) 2/7 (28.6%) 4/12 (33.3%) 2/7 (28.6%) 2/10 (20%)
    Neuropathy peripheral 1/4 (25%) 2/18 (11.1%) 0/6 (0%) 1/7 (14.3%) 5/12 (41.7%) 2/7 (28.6%) 1/10 (10%)
    Dysgeusia 1/4 (25%) 2/18 (11.1%) 3/6 (50%) 0/7 (0%) 2/12 (16.7%) 2/7 (28.6%) 1/10 (10%)
    Headache 0/4 (0%) 3/18 (16.7%) 2/6 (33.3%) 0/7 (0%) 2/12 (16.7%) 1/7 (14.3%) 1/10 (10%)
    Dysarthria 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Paraesthesia 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Syncope 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 1/10 (10%)
    Dizziness postural 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Sciatica 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Uraemic encephalopathy 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Psychiatric disorders
    Insomnia 2/4 (50%) 1/18 (5.6%) 3/6 (50%) 2/7 (28.6%) 1/12 (8.3%) 0/7 (0%) 3/10 (30%)
    Anxiety 0/4 (0%) 0/18 (0%) 2/6 (33.3%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Agitation 0/4 (0%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Confusional state 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Dysuria 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Micturition urgency 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Pollakiuria 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Haematuria 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 1/7 (14.3%) 0/10 (0%)
    Reproductive system and breast disorders
    Testicular appendage torsion 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 3/4 (75%) 1/18 (5.6%) 2/6 (33.3%) 2/7 (28.6%) 1/12 (8.3%) 0/7 (0%) 3/10 (30%)
    Cough 0/4 (0%) 2/18 (11.1%) 1/6 (16.7%) 2/7 (28.6%) 2/12 (16.7%) 0/7 (0%) 1/10 (10%)
    Dyspnoea exertional 0/4 (0%) 3/18 (16.7%) 0/6 (0%) 1/7 (14.3%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Oropharyngeal pain 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 3/12 (25%) 0/7 (0%) 0/10 (0%)
    Epistaxis 0/4 (0%) 1/18 (5.6%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 1/7 (14.3%) 0/10 (0%)
    Pleural effusion 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 1/7 (14.3%) 1/10 (10%)
    Rhinitis allergic 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 1/10 (10%)
    Rhinorrhoea 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Sinus congestion 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Hypoxia 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Nasal congestion 0/4 (0%) 0/18 (0%) 0/6 (0%) 2/7 (28.6%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Wheezing 0/4 (0%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 1/12 (8.3%) 0/7 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 1/4 (25%) 4/18 (22.2%) 1/6 (16.7%) 3/7 (42.9%) 5/12 (41.7%) 2/7 (28.6%) 1/10 (10%)
    Erythema 0/4 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 2/10 (20%)
    Dry skin 1/4 (25%) 0/18 (0%) 0/6 (0%) 1/7 (14.3%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Pruritus 0/4 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Rash maculo-papular 1/4 (25%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 2/12 (16.7%) 0/7 (0%) 0/10 (0%)
    Hyperhidrosis 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Nail discolouration 1/4 (25%) 1/18 (5.6%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Nail disorder 0/4 (0%) 2/18 (11.1%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Cold sweat 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Skin haemorrhage 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Skin hyperpigmentation 0/4 (0%) 0/18 (0%) 1/6 (16.7%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 0/10 (0%)
    Vascular disorders
    Flushing 1/4 (25%) 3/18 (16.7%) 2/6 (33.3%) 3/7 (42.9%) 1/12 (8.3%) 1/7 (14.3%) 0/10 (0%)
    Hypotension 1/4 (25%) 2/18 (11.1%) 2/6 (33.3%) 2/7 (28.6%) 0/12 (0%) 2/7 (28.6%) 1/10 (10%)
    Hypertension 0/4 (0%) 0/18 (0%) 0/6 (0%) 2/7 (28.6%) 2/12 (16.7%) 0/7 (0%) 1/10 (10%)
    Deep vein thrombosis 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)
    Hot flush 0/4 (0%) 0/18 (0%) 0/6 (0%) 0/7 (0%) 0/12 (0%) 0/7 (0%) 1/10 (10%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.

    Results Point of Contact

    Name/Title Medical Director
    Organization Takeda
    Phone +1-877-825-3327
    Email trialdisclosures@takeda.com
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT01862328
    Other Study ID Numbers:
    • C15010
    • U1111-1220-1470
    First Posted:
    May 24, 2013
    Last Update Posted:
    Jun 22, 2020
    Last Verified:
    Jun 1, 2020